Our long term objectives are: I. To characterize neurotransmitter receptors and their involvement in the mechanisms of psychopharmacologic agents, and II. To study postreceptor events involved in information transfer and in the adaptive responses to continuous drug administration such as receptor tolerance and opiate dependence. Therefore, the specific aims for the next five years will be divided in two main groups: I. Project on the Substance P Receptors. Since substance P is widely distributed in the CNS and there are indications of its involvement in several functions and in the effects of antidepressant agents, we will investigate 1) the general characteristics of the different SP receptor subtypes and the role of the SP receptor associated GTP-binding regulatory protein. 2) the relationship of SP receptor-containing neurons with antidepressant agents and with other neuronal systems. II. Project on Opiate Tolerance and Dependence. We will examine the biochemical correlates of opiate tolerance and dependence in the neuroblastoma x glioma (NG108-15) model system on the opioid receptor-adenylate cyclase complex and in the GTP-binding regulatory proteins that couple receptors to the adenylate cyclase. The specific aims will determine 1) whether opiates produce any alteration on the inhibitory GTP-binding protein or in the opiate receptor that may explain some of the mechanisms of tolerance. 2) Whether the compensatory hypertrophy of the adenylate cyclase produced by opiates is correlated to any qualitative or quantitative modification of the stimulatory GTP binding protein. 3) To examine if any of the changes seen with prolonged exposure of NG108-15 cells to opiates is also seen in opiate tolerant/dependent rats.